Limits...
A methodological framework for drug development in rare diseases.

Nony P, Kurbatova P, Bajard A, Malik S, Castellan C, Chabaud S, Volpert V, Eymard N, Kassai B, Cornu C, CRESimEpi-CRES - Orphanet J Rare Dis (2014)

Bottom Line: Developing orphan drugs is challenging because of their severity and the requisite for effective drugs.The two main objectives were (i) to provide a global strategy for each disease to identify the most relevant drugs to be evaluated in specific patients during phase III RCTs, (ii) and select the best design for each drug to be used in future RCTs.There is a need to speed up the process of orphan drug development, develop new methods for translational research and personalized medicine, and contribute to European Medicines Agency guidelines.

View Article: PubMed Central - PubMed

ABSTRACT

Introduction: Developing orphan drugs is challenging because of their severity and the requisite for effective drugs. The small number of patients does not allow conducting adequately powered randomized controlled trials (RCTs). There is a need to develop high quality, ethically investigated, and appropriately authorized medicines, without subjecting patients to unnecessary trials.

Aims and objectives: The main aim is to develop generalizable framework for choosing the best-performing drug/endpoint/design combinations in orphan drug development using an in silico modeling and trial simulation approach. The two main objectives were (i) to provide a global strategy for each disease to identify the most relevant drugs to be evaluated in specific patients during phase III RCTs, (ii) and select the best design for each drug to be used in future RCTs.

Methodological approach: In silico phase III RCT simulation will be used to find the optimal trial design and was carried out in two steps: (i) statistical analysis of available clinical databases and (ii) integrative modeling that combines mathematical models for diseases with pharmacokinetic-pharmacodynamics models for the selected drug candidates.

Conclusion: There is a need to speed up the process of orphan drug development, develop new methods for translational research and personalized medicine, and contribute to European Medicines Agency guidelines. The approach presented here offers many perspectives in clinical trial conception.

No MeSH data available.


Flow chart for modeling and simulation approach.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC4255937&req=5

Fig1: Flow chart for modeling and simulation approach.

Mentions: The methodological approach used here comprised of several steps (Table 2). For a given rare disease, the aim is to help identify the treatment that seems the most efficacious out of several potential treatments and further tested in a phase III clinical trial with an optimal experimental design in patients chosen where necessary based on specific prognostic and predictive markers. This process is done by retrospectively analyzing all available clinical databases and creating in silico (mathematical) models describing the disease, each treatment effect, and the results of clinical trials simulated in different patient populations and according to different study designs (Figure 1). The results are then ranked, according to potential efficacy, adverse events, number of patients needed, and the cost and duration of trials (Figure 2). This will allow selection of the drug(s) among old compounds to be further evaluated in a phase III trial using the most appropriate study design.Table 2


A methodological framework for drug development in rare diseases.

Nony P, Kurbatova P, Bajard A, Malik S, Castellan C, Chabaud S, Volpert V, Eymard N, Kassai B, Cornu C, CRESimEpi-CRES - Orphanet J Rare Dis (2014)

Flow chart for modeling and simulation approach.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4255937&req=5

Fig1: Flow chart for modeling and simulation approach.
Mentions: The methodological approach used here comprised of several steps (Table 2). For a given rare disease, the aim is to help identify the treatment that seems the most efficacious out of several potential treatments and further tested in a phase III clinical trial with an optimal experimental design in patients chosen where necessary based on specific prognostic and predictive markers. This process is done by retrospectively analyzing all available clinical databases and creating in silico (mathematical) models describing the disease, each treatment effect, and the results of clinical trials simulated in different patient populations and according to different study designs (Figure 1). The results are then ranked, according to potential efficacy, adverse events, number of patients needed, and the cost and duration of trials (Figure 2). This will allow selection of the drug(s) among old compounds to be further evaluated in a phase III trial using the most appropriate study design.Table 2

Bottom Line: Developing orphan drugs is challenging because of their severity and the requisite for effective drugs.The two main objectives were (i) to provide a global strategy for each disease to identify the most relevant drugs to be evaluated in specific patients during phase III RCTs, (ii) and select the best design for each drug to be used in future RCTs.There is a need to speed up the process of orphan drug development, develop new methods for translational research and personalized medicine, and contribute to European Medicines Agency guidelines.

View Article: PubMed Central - PubMed

ABSTRACT

Introduction: Developing orphan drugs is challenging because of their severity and the requisite for effective drugs. The small number of patients does not allow conducting adequately powered randomized controlled trials (RCTs). There is a need to develop high quality, ethically investigated, and appropriately authorized medicines, without subjecting patients to unnecessary trials.

Aims and objectives: The main aim is to develop generalizable framework for choosing the best-performing drug/endpoint/design combinations in orphan drug development using an in silico modeling and trial simulation approach. The two main objectives were (i) to provide a global strategy for each disease to identify the most relevant drugs to be evaluated in specific patients during phase III RCTs, (ii) and select the best design for each drug to be used in future RCTs.

Methodological approach: In silico phase III RCT simulation will be used to find the optimal trial design and was carried out in two steps: (i) statistical analysis of available clinical databases and (ii) integrative modeling that combines mathematical models for diseases with pharmacokinetic-pharmacodynamics models for the selected drug candidates.

Conclusion: There is a need to speed up the process of orphan drug development, develop new methods for translational research and personalized medicine, and contribute to European Medicines Agency guidelines. The approach presented here offers many perspectives in clinical trial conception.

No MeSH data available.